Insights into the evolution of Yersinia pestis through whole-genome comparison with Yersinia pseudotuberculosis

Abstract

Yersinia pestis, the causative agent of plague, is a highly uniform clone that diverged recently from the enteric pathogen Yersinia pseudotuberculosis. Despite their close genetic relationship, they differ radically in their pathogenicity and transmission. Here, we report the complete genomic sequence of Y. pseudotuberculosis IP32953 and its use for detailed genome comparisons with available Y. pestis sequences. Analyses of identified differences across a panel of Yersinia isolates from around the world reveal 32 Y. pestis chromosomal genes that, together with the two Y. pestis-specific plasmids, to our knowledge, represent the only new genetic material in Y. pestis acquired since the the divergence from Y. pseudotuberculosis. In contrast, 149 other pseudogenes (doubling the previous estimate) and 317 genes absent from Y. pestis were detected, indicating that as many as 13% of Y. pseudotuberculosis genes no longer function in Y. pestis. Extensive insertion sequence-mediated genome rearrangements and reductive evolution through massive gene loss, resulting in elimination and modification of preexisting gene expression pathways, appear to be more important than acquisition of genes in the evolution of Y. pestis. These results provide a sobering example of how a highly virulent epidemic clone can suddenly emerge from a less virulent, closely related progenitor.

Fig. 1.

Circular genome map of IP32953 and comparison with Y. pestis CO92. (A) Genome of IP32953. (B) Genome of CO92. (A and B) Circle 1 (from center outward), G+C content; circles 2 and 3, all genes coded by function (forward and reverse strand); circle 4, GC skew (G–C/G+C); circles 5 and 6, genome divided into locally colinear blocks (when IP32953 and CO92 are compared with one another); each block is distinguished by a unique color (black segments within colored blocks represent regions specific to that genome in the comparison), and the orientation of each block is indicated by strand; [circle 5, –ve strand; circle 6, +ve strand); circle 7, locations of IS elements (IS100 is blue, IS285 is red, IS1661 is green, and IS1541 is magenta)]. In A, the gray highlighted region near the 12 o'clock position indicates the proposed IP32953 inversion (see text), whereas the remainder of the genome denotes the stable “ancestral” arrangement that has prevailed through the present. B illustrates the complexity of the molecular events that gave rise to the inversions or translocations in the Y. pestis genome first proposed (16) solely on the basis of the dramatic shifts in G/C skew (gray highlights serotypes I, II, and III), but now extended through whole-genome comparison. For example, gray highlight II is composed of three distinct blocks, two that are derived from distinct places within the same replichore (origin to terminus half), whereas the third block originated from the other replichore (light blue block).

Fig. 2.

Functional classification of genes missing or inactivated in Y. pestis. Distribution of Y. pestis-specific lost functions by gene region deletion (light blue) or by gene inactivation (i.e., pseudogene, dark purple) in COG functional groups: C, energy production; D, cell division and/or chromosome partitioning; E, amino acid metabolism; F, nucleotide metabolism; G, carbohydrate metabolism; H, coenzyme metabolism; I, lipid metabolism; J, translation; K, transcription; L, DNA replication and/or repair; M, cell envelope biogenesis; N, cell motility, secretion; O, posttranslational modification; P, inorganic ion metabolism; R, general function prediction only; S, function unknown; T, signal transduction; conserved, conserved hypothetical genes with no significant COG hits; and unique, hypothetical genes with no significant COG hit.